肿瘤干细胞与肿瘤微环境相互作用的研究进展_West China Medical Journal

Authors：

 喻杨 , 王喻义 , 王乙钦 ,  蒋明

四川大学华西医院肿瘤中心肿瘤一病房（成都 610041）;

Corresponding author：

喻杨, Email: 183932834@qq.com; 蒋明, Email: 307048372@qq.com

Keywords：

肿瘤干细胞; 微环境; 血管形成; 细胞外基质; 低氧

DOI：

10.7507/1002-0179.20150511

Video：

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肿瘤干细胞作为肿瘤发生、发展、复发、耐药的根源，在近些年受到广泛关注。随着研究的不断深入，人们慢慢发现，肿瘤干细胞与肿瘤微环境在肿瘤发展过程中进行着复杂的对话，肿瘤干细胞不仅可以适应肿瘤微环境的变化，还可以改变、影响肿瘤微环境；而肿瘤微环境不仅可以影响干细胞的自我更新能力，还可以诱导正常小细胞和非肿瘤干细胞向肿瘤干细胞转变。

Citation： 喻杨, 王喻义, 王乙钦, 蒋明. 肿瘤干细胞与肿瘤微环境相互作用的研究进展. West China Medical Journal, 2015, 30(9): 1784-1788. doi: 10.7507/1002-0179.20150511 Copy

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2.	Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell[J]. Nat Med, 1997, 3(7):730-737.
3.	Wang R, Chadalavada K, Wilshire J, et al. Glioblastoma stem-like cells give rise to tumour endothelium[J]. Nature, 2010, 468(7325):829-833.
4.	Chaffer CL, Brueckmann I, Scheel C, et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state[J]. Proc Natl Acad Sci USA, 2011, 108(19):7950-7955.
5.	Korkaya H, Liu S, Wicha MS. Breast cancer stem cells, cytokine networks, and the tumor microenvironment[J]. J Clin Invest, 2011, 121(10):3804-3809.
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8.	Grivennikov SI, Greten FR, Immunity KM. Inflammation, and cancer[J]. Cell, 2010, 140(6):883-899.
9.	Dvorak HF. Tumors:wounds that do not heal. Similarities between tumor stroma generation and wound healing[J]. N Engl J Med, 1986, 315(26):1650-1659.
10.	Yang X, Hou J, Han Z, et al. One cell, multiple roles:contribution of mesenchymal stem cells to tumor development in tumor microenvironment[J]. Cell Biosci, 2013, 3(1):5.
11.	Bianchi G, Borgonovo G, Pistoia V, et al. Immunosuppressive cells and tumour microenvironment:focus on mesenchymal stem cells and myeloid derived suppressor cells[J]. Histol Histopathol, 2011, 26(7):941-951.
12.	Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells[J]. Science, 1999, 284(5411):143-147.
13.	Shinojima N, Hossain A, Takezaki T, et al. TGF-β mediates homing of bone marrow-derived human mesenchymal stem cells to glioma stem cells[J]. Cancer Res, 2013, 73(7):2333-2344.
14.	Liu S, Ginestier C, Ou SJ, et al. Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks[J]. Cancer Res, 2011, 71(2):614-624.
15.	Li HJ, Reinhardt F, Herschman HR, et al. Cancer-stimulated mesenchymal stem cells create a carcinoma stem cell niche via prostaglandin E2 signaling[J]. Cancer Discov, 2012, 2(9):840-855.
16.	Mclean K, Gong Y, Choi Y, et al. Human ovarian carcinoma-associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production[J]. J Clin Invest, 2011, 121(8):3206-3219.
17.	Gabbiani G, Majno G. Dupuytren's contracture:fibroblast contraction? An ultrastructural study[J]. Am J Pathol, 1972, 66(1):131-146.
18.	Farmer P, Bonnefoi H, Anderle P, et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer[J]. Nat Med, 2009, 15(1):68-74.
19.	Finak G, Bertos N, Pepin F, et al. Stromal gene expression predicts clinical outcome in breast cancer[J]. Nat Med, 2008, 14(5):518-527.
20.	Vermeulen L, Melo FD, Van Der Heijden M, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment[J]. Nat Cell Biol, 2010, 12(5):468-U121.
21.	Fillmore CM, Gupta PB, Rudnick JA, et al. Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling[J]. Proc Natl Acad Sci USA, 2010, 107(50):21737-21742.
22.	Orimo A, Gupta PB, Sgroi DC, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion[J]. Cell, 2005, 121(3):335-348.
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24.	Mantovani A, Sica A. Macrophages, innate immunity and cancer:balance, tolerance, and diversity[J]. Curr Opin Immunol, 2010, 22(2):231-237.
25.	Fischer C, Jonckx B, Mazzone M, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels[J]. Cell, 2007, 131(3):463-475.
26.	Mitchem JB, Brennan DJ, Knolhoff BL, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses[J]. Cancer Res, 2013, 73(3):1128-1141.
27.	Fan QM, Jing YY, Yu GF, et al. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma[J]. Cancer Lett, 2014, 352(2):160-168.
28.	Yang J, Liao D, Chen C, et al. Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway[J]. Stem Cells, 2013, 31(2):248-258.
29.	Ding J, Jin W, Chen C, et al. Tumor associated macrophage×cancer cell hybrids May acquire cancer stem cell properties in breast cancer[J]. PLoS One, 2012, 7(7):e41942.
30.	Jinushi M, Chiba S, Yoshiyama HA, et al. Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells[J]. Proc Natl Acad Sci USA, 2011, 108(30):12425-12430.
31.	Yu X, Li H, Ren X. Interaction between regulatory T cells and cancer stem cells[J]. Int J Cancer, 2012, 131(7):1491-1498.
32.	Peñuelas S, Anido J, Prieto-Sánchez RM, et al. TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma[J]. Cancer Cell, 2009, 15(4):315-327.
33.	Wei J, Barr J, Kong LY, et al. Glioma-associated cancer-initiating cells induce immunosuppression[J]. Clin Cancer Res, 2010, 16(2):461-473.
34.	Kerbel RS. Tumor angiogenesis[J]. N Engl J Med, 2008, 358(19):2039-2049.
35.	Ping YF, Bian XW. Consice review:contribution of cancer stem cells to neovascularization[J]. Stem Cells, 2011, 29(6):888-894.
36.	Bhati R, Patterson C, Livasy CA, et al. Molecular characterization of human breast tumor vascular cells[J]. Am J Pathol, 2008, 172(5):1381-1390.
37.	Bao S, Wu Q, Sathornsumetee S, et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor[J]. Cancer Res, 2006, 66(16):7843-7848.
38.	Grange C, Tapparo M, Collno F, et al. Microvesicles released from human renal cancer stem cells stiulate angiogenesis and formation of lung pre-metastatic niche[J]. Cancer Res, 2011, 71(15):5346-5356.
39.	Folkins C, Shaked Y, Man S, et al. Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1[J]. Cancer Res, 2009, 69(18):7243-7251.
40.	Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells[J]. Cancer Cell, 2007, 11(1):69-82.
41.	Pàez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis[J]. Cancer Cell, 2009, 15(3):220-231.
42.	Lyden D, Hattori K, Dias S, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth[J]. Nat Med, 2001, 7(11):1194-1201.
43.	Lu P, Weaver VM, Werb Z. The extracellular matrix:a dynamic niche in cancer progression[J]. J Cell Biol, 2012, 196(4):395-406.
44.	Lu P, Takai K, Weaver VM, et al. Extracellular matrix degradation and remodeling in development and disease[J]. Cold Spring Harb Perspect Biol, 2011, 3(12):pii:a005058.
45.	Wong GS, Rustgi AK. Matricellular proteins:priming the tumour microenvironment for cancer development and metastasis[J]. Br J Cancer, 2013, 108(4):755-761.
46.	Li L, Cole J, Margolin DA. Cancer stem cell and stromal microenvironment[J]. Ochsner J, 2013, 13(1):109-118.
47.	Li L, Xie T. Stem cell niche:structure and function[J]. Annu Rev Cell Dev Biol, 2005, 21:605-631.
48.	Casazza A, Di Conza G, Wenes M, et al. Tumor stroma:a complexity dictated by the hypoxic tumor microenvironment[J]. Oncogene, 2014, 33(14):1743-1754.
49.	Li P, Zhou C, Xu L, et al. Hypoxia enhances stemness of cancer stem cells in glioblastoma:an in vitro study[J]. Int J Med Sci, 2013, 10(4):399-407.
50.	Keith B, Simon MC. Hypoxia-inducible factors, stem cells, and cancer[J]. Cell, 2007, 129(3):465-472.
51.	Raval RR, Lau KW, Tran MG, et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma[J]. Mol Cell Biol, 2005, 25(13):5675-5686.
52.	Covello KL, Kehler J, Yu H, et al. HIF-2alpha regulates Oct-4:effects of hypoxia on stem cell function, embryonic development, and tumor growth[J]. Genes Dev, 2006, 20(5):557-570.
53.	Meissner A, Wernig M, Jaenisch R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells[J]. Nat Biotechnol, 2007, 25(10):1177-1181.
54.	Conley SJ, Gheordunescu E, Kakarala P, et al. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia[J]. Proc Natl Acad Sci USA, 2012, 109(8):2784-2789.
55.	Gustafsson MV, Zheng X, Pereira T, et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state[J]. Dev Cell, 2005, 9(5):617-628.
56.	Heddleston JM, Li Z, Mclendon RE, et al. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype[J]. Cell Cycle, 2009, 8(20):3274-3284.

1. Hanahan D, Weinberg RA. Hallmarks of cancer:the next generation[J]. Cell, 2011, 144(5):646-674.
2. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell[J]. Nat Med, 1997, 3(7):730-737.
3. Wang R, Chadalavada K, Wilshire J, et al. Glioblastoma stem-like cells give rise to tumour endothelium[J]. Nature, 2010, 468(7325):829-833.
4. Chaffer CL, Brueckmann I, Scheel C, et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state[J]. Proc Natl Acad Sci USA, 2011, 108(19):7950-7955.
5. Korkaya H, Liu S, Wicha MS. Breast cancer stem cells, cytokine networks, and the tumor microenvironment[J]. J Clin Invest, 2011, 121(10):3804-3809.
6. Polyak K, Haviv I, Campbell IG. Co-evolution of tumor cells and their microenvironment[J]. Trends Genet, 2009, 25(1):30-38.
7. Coussens LM, Werb Z. Inflammation and cancer[J]. Nature, 2002, 420(6917):860-867.
8. Grivennikov SI, Greten FR, Immunity KM. Inflammation, and cancer[J]. Cell, 2010, 140(6):883-899.
9. Dvorak HF. Tumors:wounds that do not heal. Similarities between tumor stroma generation and wound healing[J]. N Engl J Med, 1986, 315(26):1650-1659.
10. Yang X, Hou J, Han Z, et al. One cell, multiple roles:contribution of mesenchymal stem cells to tumor development in tumor microenvironment[J]. Cell Biosci, 2013, 3(1):5.
11. Bianchi G, Borgonovo G, Pistoia V, et al. Immunosuppressive cells and tumour microenvironment:focus on mesenchymal stem cells and myeloid derived suppressor cells[J]. Histol Histopathol, 2011, 26(7):941-951.
12. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells[J]. Science, 1999, 284(5411):143-147.
13. Shinojima N, Hossain A, Takezaki T, et al. TGF-β mediates homing of bone marrow-derived human mesenchymal stem cells to glioma stem cells[J]. Cancer Res, 2013, 73(7):2333-2344.
14. Liu S, Ginestier C, Ou SJ, et al. Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks[J]. Cancer Res, 2011, 71(2):614-624.
15. Li HJ, Reinhardt F, Herschman HR, et al. Cancer-stimulated mesenchymal stem cells create a carcinoma stem cell niche via prostaglandin E2 signaling[J]. Cancer Discov, 2012, 2(9):840-855.
16. Mclean K, Gong Y, Choi Y, et al. Human ovarian carcinoma-associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production[J]. J Clin Invest, 2011, 121(8):3206-3219.
17. Gabbiani G, Majno G. Dupuytren's contracture:fibroblast contraction? An ultrastructural study[J]. Am J Pathol, 1972, 66(1):131-146.
18. Farmer P, Bonnefoi H, Anderle P, et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer[J]. Nat Med, 2009, 15(1):68-74.
19. Finak G, Bertos N, Pepin F, et al. Stromal gene expression predicts clinical outcome in breast cancer[J]. Nat Med, 2008, 14(5):518-527.
20. Vermeulen L, Melo FD, Van Der Heijden M, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment[J]. Nat Cell Biol, 2010, 12(5):468-U121.
21. Fillmore CM, Gupta PB, Rudnick JA, et al. Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling[J]. Proc Natl Acad Sci USA, 2010, 107(50):21737-21742.
22. Orimo A, Gupta PB, Sgroi DC, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion[J]. Cell, 2005, 121(3):335-348.
23. Jung MJ, Rho JK, Kim YM, et al. Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells[J]. Oncogene, 2013, 32(2):209-221.
24. Mantovani A, Sica A. Macrophages, innate immunity and cancer:balance, tolerance, and diversity[J]. Curr Opin Immunol, 2010, 22(2):231-237.
25. Fischer C, Jonckx B, Mazzone M, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels[J]. Cell, 2007, 131(3):463-475.
26. Mitchem JB, Brennan DJ, Knolhoff BL, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses[J]. Cancer Res, 2013, 73(3):1128-1141.
27. Fan QM, Jing YY, Yu GF, et al. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma[J]. Cancer Lett, 2014, 352(2):160-168.
28. Yang J, Liao D, Chen C, et al. Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway[J]. Stem Cells, 2013, 31(2):248-258.
29. Ding J, Jin W, Chen C, et al. Tumor associated macrophage×cancer cell hybrids May acquire cancer stem cell properties in breast cancer[J]. PLoS One, 2012, 7(7):e41942.
30. Jinushi M, Chiba S, Yoshiyama HA, et al. Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells[J]. Proc Natl Acad Sci USA, 2011, 108(30):12425-12430.
31. Yu X, Li H, Ren X. Interaction between regulatory T cells and cancer stem cells[J]. Int J Cancer, 2012, 131(7):1491-1498.
32. Peñuelas S, Anido J, Prieto-Sánchez RM, et al. TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma[J]. Cancer Cell, 2009, 15(4):315-327.
33. Wei J, Barr J, Kong LY, et al. Glioma-associated cancer-initiating cells induce immunosuppression[J]. Clin Cancer Res, 2010, 16(2):461-473.
34. Kerbel RS. Tumor angiogenesis[J]. N Engl J Med, 2008, 358(19):2039-2049.
35. Ping YF, Bian XW. Consice review:contribution of cancer stem cells to neovascularization[J]. Stem Cells, 2011, 29(6):888-894.
36. Bhati R, Patterson C, Livasy CA, et al. Molecular characterization of human breast tumor vascular cells[J]. Am J Pathol, 2008, 172(5):1381-1390.
37. Bao S, Wu Q, Sathornsumetee S, et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor[J]. Cancer Res, 2006, 66(16):7843-7848.
38. Grange C, Tapparo M, Collno F, et al. Microvesicles released from human renal cancer stem cells stiulate angiogenesis and formation of lung pre-metastatic niche[J]. Cancer Res, 2011, 71(15):5346-5356.
39. Folkins C, Shaked Y, Man S, et al. Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1[J]. Cancer Res, 2009, 69(18):7243-7251.
40. Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells[J]. Cancer Cell, 2007, 11(1):69-82.
41. Pàez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis[J]. Cancer Cell, 2009, 15(3):220-231.
42. Lyden D, Hattori K, Dias S, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth[J]. Nat Med, 2001, 7(11):1194-1201.
43. Lu P, Weaver VM, Werb Z. The extracellular matrix:a dynamic niche in cancer progression[J]. J Cell Biol, 2012, 196(4):395-406.
44. Lu P, Takai K, Weaver VM, et al. Extracellular matrix degradation and remodeling in development and disease[J]. Cold Spring Harb Perspect Biol, 2011, 3(12):pii:a005058.
45. Wong GS, Rustgi AK. Matricellular proteins:priming the tumour microenvironment for cancer development and metastasis[J]. Br J Cancer, 2013, 108(4):755-761.
46. Li L, Cole J, Margolin DA. Cancer stem cell and stromal microenvironment[J]. Ochsner J, 2013, 13(1):109-118.
47. Li L, Xie T. Stem cell niche:structure and function[J]. Annu Rev Cell Dev Biol, 2005, 21:605-631.
48. Casazza A, Di Conza G, Wenes M, et al. Tumor stroma:a complexity dictated by the hypoxic tumor microenvironment[J]. Oncogene, 2014, 33(14):1743-1754.
49. Li P, Zhou C, Xu L, et al. Hypoxia enhances stemness of cancer stem cells in glioblastoma:an in vitro study[J]. Int J Med Sci, 2013, 10(4):399-407.
50. Keith B, Simon MC. Hypoxia-inducible factors, stem cells, and cancer[J]. Cell, 2007, 129(3):465-472.
51. Raval RR, Lau KW, Tran MG, et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma[J]. Mol Cell Biol, 2005, 25(13):5675-5686.
52. Covello KL, Kehler J, Yu H, et al. HIF-2alpha regulates Oct-4:effects of hypoxia on stem cell function, embryonic development, and tumor growth[J]. Genes Dev, 2006, 20(5):557-570.
53. Meissner A, Wernig M, Jaenisch R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells[J]. Nat Biotechnol, 2007, 25(10):1177-1181.
54. Conley SJ, Gheordunescu E, Kakarala P, et al. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia[J]. Proc Natl Acad Sci USA, 2012, 109(8):2784-2789.
55. Gustafsson MV, Zheng X, Pereira T, et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state[J]. Dev Cell, 2005, 9(5):617-628.
56. Heddleston JM, Li Z, Mclendon RE, et al. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype[J]. Cell Cycle, 2009, 8(20):3274-3284.

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肿瘤干细胞与肿瘤微环境相互作用的研究进展

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